Amino substituted phenyl and naphthyl esters of PGF{HD 2{301 {B - type compounds

ABSTRACT

Substituted phenyl and naphthyl esters of PGF2 Alpha , 15-alkylPGF2 Alpha , and 15(R)-15-alkyl-PGF2 Alpha , and their racemic forms, and processes for producing them are disclosed. The products are useful for the same pharmacological and medical purposes as PGF2 Alpha , 15-alkyl-PGF2 Alpha , and 15(R)-15alkyl-PGF2 Alpha , and are also useful as a means for obtaining highly purified PGF2 Alpha , 15-alkyl-PGF2 Alpha , and 15(R)-15alkyl-PGF2 Alpha products.

United States Patent [1 1 Morozowich AMINO SUBSTITUTED PIIENYL AND NAPHTHYL ESTERS OF PGF TYPE COMPOUNDS [75] Inventor: Walter Morozowich, Kalamazoo,

Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

[22] Filed: Jan. 8, 1974 [21] Appl. No.: 431,758

[52] US. Cl 260/468 I); 260/395; 260/463; I

260/471 R; 260/473 R; 260/476; 260/514 D; 424/305; 424/308; 424/309 [51] Int. Cl C07c 69/74; C07c 103/38 [58] Field of Search 260/468 [56] References Cited FOREIGN PATENTS OR APPLICATIONS 775,106 3/1972 Belgium 260/468 June 17, 1975 OTHER PUBLICATIONS Fieser et al., Reagent for Organic Synthesis, volume 1, pp. 86, 1229, (1967).

Primary ExaminerRobert Gerstl Attorney, Agent, or Firm-Morris L. Nielsen [5 7] ABSTRACT 6 Claims, N0 Drawings 1 2 AMINO SUBSTITUTED PHENYL AND NAPHTHYL methyl-PGF a (E. W. Yankee et al., J. Am. Chem. Soc.

ESTERS OF PGF a TYPE COMPOUNDS 94, 3651 (1972)). the phenyl, alkyl-phenyl, and 1- naphthyl esters of PGF a (British patent specification BACKGROUND OF THE INVENTION No. 1,040,544, see Derwent Farmdoc. No. 22,599),

This invention relates to novel ester derivatives of 5 and the a-naphthyl ester of PGF a (Belgian Pat. No. prostaglandin F 01 (hereinafter identified as PGF a), 775,106, see Derwent Farmdoc No. 33705T). 15-alkyl-PGF oz, 15(R)-15-alkyl-PGF a, and their racemie forms, and to processes for producing them. SUMMARY OF THE INVENTION PGF a is represented by the formula: It is a purpose of this invention to provide novel ester derivatives of prostaglandin PGF a, l5-alkyl-PGF a,

l5(R)-15-alkyl-PGF a, and their racemic forms. It is a further purpose to provide such esters derived from x COOH substituted phenols and naphthols, and hydroxyfluoroenone. It is a further purpose to provide such esters in a free-flowing crystalline form. It is'still a further purpose to provide novel processes for preparing these HO H OH esters.

The presently described esters include compounds represented by the generic formula:

A systematic name for PGF a is 7-{3a,5a-dihydroxy- 2,B-[(3S)-3-hydroxy-trans-l-octenyl}la-cyclopentyl}- 2O O cis-5-heptenoic acid. PGF a is known to be useful for R H a variety of pharmacological and medical purposes, for IH C 2 )s-C- -Z example labor induction and abortion in pregnant ani- =C mals, including humans, menstrual regulation in both 75 H v pregnant and non-pregnant animals, including humans, H and reduction and control of gastric secretion. See I Bergstrom et al., Pharmacol, Rev. 20, l (1968) and ref- (CH2 FCHS erenees cited therein. As to racemic PGF a, see for example E. S. Corey et al., J. Am. Chem. Soc., 91,5675 Y (1969).

The lS-aIkyl-PGF- Q analog and its 15(R) epimer are wherein Z is the substituted phenyl or naphthyl group represented by the formula: or fluorenone as defined immediately below, and Y is H 0H, CH3 0H, C2H5 OH, CH3 OH, or. C2H5 OH,

i.e. esters of PGF- oz, l5-methyl-PGF oz l5(R)-l5- 40 PGF a; and also the racemic compounds represented by each respective formula and the mirror image thereof; Z being represented by -NH-C-CH wherein Y is v 3 I I A I I CH3 OH, Ca i l5 OH, CH3 OH, 01'' C H5 OH, O 1

following the usual convention wherein broken line attachment of hydroxy to the side chain at carbon 15 indicates the natural or S configuration and solid line attachment of hydroxy indicates the epi or R configuration. See for example Nugteren et al., Nature 212, O O 38(1966)and Cahn,J. Chem. Ed.4l, 116(1964).The U Ll l5-alkyland l5(R)-l5-alkyl-PGF a analogs in their '@-NH -CH optically active and racemic forms are known. See for example US. Pat. No. 3,728,382. These analogs are also useful for the above-described pharmacological O O purposes. H u

Esters of the above compounds are known, wherein -NH-C--NH- the hydrogen atom of the carboxyl group is replaced by a hydrocarbyl or substituted hydrocarbyl group. Among these are the methyl ester of PGF a (B. Sam- O uelsson, J. Biol. Chem. 238, 3229 (1963)), the methyl ester of racemic PGF a(E. J. Corey et al., J. Am. E Chem. Soc. 91, 5675 (1969)), the methyl ester of 15- and Z is A, i.e.

wherein Y is CH3 H and Z iS B, i..

including of course not only the optically active isomer represented by formula [II but also its mirror image.

The novel formula-ll] compounds and corresponding racemic compounds of this invention are each useful for the same purposes as described above for PGFZOK and are used for those purposes in the same manner known in the art, including oral, sublingual, buccal, rectal, intravaginal, intrauterine, or topical administration. 5

For many applications these novel prostaglandin esters which I have obtained from certain specified phenols, naphthols, and hydroxyfluorenone have advantages over the corresponding known prostaglandin compounds. In oral administration these esters have 0 shown surprisingly greater efficacy than the corresponding free acids or lower alkyl esters, whether because of longer duration of biological activity or because of improved lipophilicity and absorption is not certain. These esters offer a further advantage in that they have low solubility in water and the body fluids and are therefore retained longer at the site of administration.

A particularly outstanding advantage of many of these substituted phenyl and naphthyl and hydroxyfluorenone esters is that they'are obtained in freeflowing crystalline form, generally of moderately high melting point, in the range 90l 80C. This form is especially desirable for ease of handling, administering, and purifying.

These crystalline esters also provide a means of purifying PGF a, IS-methyl-PGF a, I5(R)-l5-methyl- PGF a, l5-ethyl-PGF a, or l5(R)-15-ethyl-PGF a, which are first converted to one of these esters, recrystallized until pure, and then recovered as the free acid. t

One method of recovering the free acid is by enzymatic hydrolysis of the ester, for example with a lipase. See German Pat. No. 2,242,792, Derwent Farmdoc No. 23047u.

To obtain the optimum combination of stability, duration of biological activity, lipophilicity, solubility, and crystallinity, certain compounds within the scope of formula III are preferred.

One preference is that Z is limited to either g is t NH-C-CHa SOZNHQ ll NH-C-CH-a i OI" Another preference is that Z is further limited to wherein R is I 0 ll -Q 'NHZ OF -NH-CCH or NH- C-CHQ NH- -R wherein R is Another preference is that Z is limited to v I |O| ;H2-IcH-c'-NH NH fi-v-CH cells wherein R is -NH--C-lCeHsls or -OCH3;

O ll @O-C-R wherein R is O ll @ttwt.

Especially preferred are those compounds which are in free-flowing crystalline form, including:

p-acetamidophenyl ester of PGF a p-benzamidophenyl ester of PGF a p-ureidophenyl ester of PGF a p-(3-phenylureido)phenyl ester of PGF a 4-biphenylyl ester of PGF a p-tritylphenyl ester of PGF- oz p-(2-acetamido-2-carbamoylethyl)phenyl PGFzOl p-(2-benzamido-Z-carbamoylethyl)phenyl ester of PGF o: a-semicarbazono-p-tolyl ester of PGF a BSIBI' p-acetylphenyl ester of PGF a p-benzoylphenyl ester of PGF a p-carbamoylphenyl ester of PGF a o-carbamoylphenyl ester of PGF a p-(methoxycarbonyhphenyl ester of PGF a Z-naphthyl ester of PGF a 5-sulfamoyl-l-naphthyl ester of PGF a The substituted phenyl and naphthyl and 9- oxofluoren-4yl esters of PGF-gd, l5-alkyl-PGF oz, and 15(R)-15-alkyl-PGF a encompassed by formula 111 wherein Z is defined by ester groups A through Z are produced by the reactions and procedures described and exemplified hereinafter. For convenience. the above prostaglandin or prostaglandin analog is referred to as the PG compound". The term phenol is used in a generic sense, for the hydroxy compounds, including phenols, naphthols, and hydroxyfluorenone.

Various methods are available for preparing these esters, differing as to yield and purity of product. Thus, by one method, the PG compound is converted to a tertiary amine salt, reacted with pivaloyl halide to give the mixed acid anhydride and then reacted with the phenol. Alternately, instead of pivaloyl halide, analkyl or phenylsulfonyl halide is used, such as p-toluenes ulfonyl chloride. See for example Belgian Pat. N0s. 77 5,l06 and 776,294, Derwent Farmdoc Nos. 33705T and 3901 IT.

Still another method is by the use of the coupling reagent, dicyclohexylcarbodiimide. See Fieser et al., Reagents for Organic Synthesis, pp, 231-236, John Wiley and Sons, lnc., New York (1967). The PG compound is contacted with 1 to 10 molar equivalents of the phenol in the presence of 2-10 molar equivalents of dicyclohexylcarbodiimide in pyridine as a solvent.

The preferred novel process for the preparation of these esters, however. comprises the steps (1) forming a mixed anhydride with the PG compound and isobutylchloroformate in the presence of a tertiary amine and (2) reacting the anhydride with an appropriate phenol or naphthol.

The mixed anhydride is represented by the formula:

for the optically active PG compounds, Y having the same definition as above.

The anhydride is formed readily at temperatures in the range 40 to +60 C., preferably at 10 to +10 C. so that the rate is reasonably fast and yet side reactions are minimized. The isobutylchloroformate reagent is preferably used in excess, for example 1.2 molar equivalents up to 4.0 per mole of the PG compound. The reaction is preferably done in a solvent and for this purpose acetone is preferred, although other relatively non-polar solvents are used such as acetonitrile, dichloromethane, and chloroform. The reaction is run in the presence of a tertiary amine, for example triethylaminc, and the co-formed amine hydrochloride usually crystallizes out, but need not be removed for the next step.

The anhydride is usually not isolated but is reacted directly in solution with the phenol, preferably in the presence of a tertiary amine such as pyridine.

The phenol is preferably used in equivalent amounts or in excess to insure that all of the mixed anhydride is converted to ester. Excess phenol is separated from the product by methods described herein or known in the art, for example by crystallization. The tertiary amine is not only a basic catalyst for the esterification but also a convenient solvent. Other examples of tertiary amines useful for this purpose include N- methylmorpholine, triethylamine, diisopropylethylamine, and dimethylaniline. Although they may be used, 2-methylpyridine and quinoline result in a slow reaction. A highly hindered amine such as 2,6-v dimethyllutidine is not useful because of the slowness of the reaction.

The reaction with the anhydride proceeds smoothly at room temperature (about to 30 C.) and can be followed in the conventional manner with thin layer chromatography (TLC), usually being found complete within 1-4 hours.

The reaction mixture is worked up to yield the ester following methods known in the art, and the product'is purified, for example by silica gel chromatography.

Solid esters are converted to a free-flowing crystalline form on crystallization from a variety of solvents, including ethyl acetate, tetrahydrofuran, methanol, and acetone, by cooling or evaporating a saturated solution of the ester in the solvent or by adding a miscible nonsolvent such as diethyl ether, hexane, or water. The crystals are then collected by conventional techniques, eg filtration or centrifugation, washed with a small amount of solvent, and dried under reduced pressure. They may also be dried in a current of warm nitrogen or argon, or by warming to about 75 C. Although the crystals are normally pure enough for many applications, they may be recrystallized by the same general techniques to achieve improved purity after each recrystallization.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The invention can be more fully understood by the following examples.

All temperatures are in degrees Centigrade.

Silica gel chromatography, as used herein, is understood to include chromatography on a column packed with silica gel, elution, collection of fractions, and combination of those fractions shown by thin layer chromatography (TLC) to contain thedesired product free of 55 starting material and impurities.

TLC, herein, refers to thin layer chromatography.

PREPARATION l p-Benzamidophenol A solution of p-hydroxyaniline (20 g.) in 200 ml. of pyridine is treated with benzoic anhydride (20 g.). After 4 hr. at about C., the mixture is concentrated under reduced pressure and the residue is taken up in 200 ml. of hot methanol and reprecipitated with 300 65 ml. of water. The product is recrystallized from hot acetonitrile as white crystals, 8.5 g., m.p. 2l8.02l8.5 C.

PREPARATION 2 p-(p-Acetamidobenzamido )phenol A solution of p-acetamidobenzoic acid (12.5 g.) in 250 ml. of tetrahydrofuran is treated with triethylamine (ll.l ml.).The mixture is then treated with isobutylchloroformate (10.4 ml.) and, after 5 min. at about 25 C., with p-aminophenol (13.3 g.) in ml. of dry pyridine. After 40 min. the crude product is obtained by addition of 2 liters of water. The product is recrystallized from 500 ml. of hot methanol by dilution with 300 ml. of water white crystals. 5.9 g., m.p. 275.0277.0 C.

EXAMPLE 1 p-Acetamidophenyl Ester of PGF a (Formula III-A) A solution of PGF a (0.535 g.) and triethylamine (0.254 ml.) in 20 ml. of acetone is treated at l0 C. with isobutylchloroformate (0.238 ml.) whereupon triethylamine hydro'chlor'id'efiisprecipitated. After 5 min. the mixture is treated with p-acetamidophenol (0.342

g.) in 5 ml. of pyridine for 3 hr.at about 25 C. The solp-Benzamidophenyl Ester of PGF- a (Formula Ill-B) Following the procedure of Example 1 but using 0.535 g. of PGF a, 0.254 ml. of triethylamine, 0.238 ml. of isobutylchloroformate, and 0.48] g. of pbenzamidophenol (Preparation -1 there is obtained a' V crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate followed by ethyl acetate-methanol (:5 The residue obtained by concentration of selected fractions, 0.220 g., is crystallized from ethyl acetate-methanol :5) diluted with hexane as the title compound, white free-flowing crystals, m.p. l39.8l43.8 C., having R, O.8 (TLC on silica gel in ethyl acetate-methanol (9525)).

EXAMPLE 3 p-Ureidophenyl Ester'of PGF a (Formula III-E) Following the procedure of Example 1 but using 0.738 'g. of PGF a, 0.306 ml. of triethylamine, 0.288 ml. of isobutylchloroformate, and 0.330 g. of phydroxyphenylurea, there is obtained a crude residue.

This residue is subjected to silica gel chromatography, eluting' with ethyl acetateacetone (4:1). The residue obtained by concentration of selected fractions, 0.488

g., is crystallized from acetone diluted with one-half the volume of hexane as the title compound, white freeflowing crystals, m.p. l33.8-l35.0 C. having R; 0.5

(TLC on silica gel in ethyl acetate-acetone (411).. I

EXAMPLE 4 p-(3-Phenylureido)phenyl Ester of PGF a (Formula III-F) Following the procedure of Example 1 but using 0.738 g. of PGF oz, 0.347 ml. of triethylamine, 0.326 ml. of isobutylchloroformate, and 0.705 g. of phydroxy-l,3-dipheny1urea, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-acetone (7:3). The residue obtained by concentration of selected fractions, 0.475 g., is crystallized from hot ethyl acetate as the title compound, white free-flowing crystals, m.p. l45.0147.3 C, having R 0.42 (TLC on silica gel in ethyl acetate-acetone (7:3).

EXAMPLE 5 p'Biphenyl Ester ofPGF a (Formula lll-G) Following the procedure of Example 1 but using 0.535 g. of PGF a, 0.254 ml. of triethylamine, 0.238 ml. of isobutylchloroformate, and 0.385 g. of pphenylphenol, there is obtained acrude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate followed by acetonitrile. The residue obtained by concentration of selected fractions, 0.270 g., is crystallized from ethyl acetate diluted with an equal volume of hexane as the title compound, white free-flowing crystals, m.p. l14.31l6.8 C. having R; 0.25 (TLC on silica gel in ethyl acetate).

EXAMPLE 6 p-Tritylphenyl Ester of PGF a (Formula lll-H) Following the procedure of Example 1 but using 0.738 g. of PGF a, 0.291 ml. of triethylamine, 0.275 ml. of isobutylchloroformate, and 0.840 g. of ptritylphenol, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-water (99:1 The residue obtained by concentration of selected fractions, 0.576 g., is crystallized from acetone diluted with five volumes of hexane as the title compound, white free-flowing crystals, m.p. l23.8129.0, having 11 0.5 (TLC on silica gel in ethyl acetate).

EXAMPLE 7 p-(2-Acetamido-2-carbamoylethyl)phenyl Ester of PGF OL (Formula Ill-l) Following the procedure of Example 1 but using 0.738 g. of PGF a, 0.306 ml. of triethylamine, 0.288 ml. of isobutylchloroformate, and 0.488 g. of N-acetyl- L-tyrosinamide, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting successively with ethyl acetate-methanol-water (90:10:1) and ethyl acetate-methanolwater (80:20:1). The major fraction is chromatographed again, eluting with ethyl acetate-methanol (4:1). The residue obtained by concentration of selected fractions, 0.242 g.

is crystallized from acetone diluted with 1.5 volumes of hexane as the title compound, white free-flowing crystals, m.p. l09.8l13.8 with softening at l05.0 having R; 0.5 (TLC on silica gel in ethyl acetate-methanol (4:1)).

EXAMPLE 8 p-(2-13enzamido-Z-carbamoylethyl)phenyl Ester of PGF a (Formula ll1J) Following the procedure of Example l but using 0.738 g. of 1 0F 04, 0.306 ml. of triethylamine, 0.288 ml. of isobutylchloroformate, and 0.625 g. of N-benzoyl-L-tyrosinamide, there is obtained a crude residue. This residue is subjected to silica gel chromatography,

eluting with ethyl acetate-tetrahydrofuran-water (60:40:1). The residue obtained by concentration of selected fractions. 0.459 g., is crystallized from hot acetonitrile as the title compound, white free-flowing crysta1s,m.p. 142.5144.3 C., having R,0.5 (TLC on silica gel in ethyl acetate-tetrahydrofuran (3:2)).

EXAMPLE 9 ot-Semicarbazono-p-tolyl Ester of PGF oz (Formula Ill-K) Following the procedure of Example 1 but using 0.535g. of PGF a, 0.254 ml. of triethylamine, 0.238 ml. of isobutylchloroformate, and 0.405 g. of phydroxybenzaldehyde semicarbazone, there is obtained a crude residue, This residue is subjected to silica gel chromatography, eluting with ethyl acetate-methanol (9:1) and ethyl acetate-methanol (8:2 The residue obtained by Concentration of selected fractions, 0.215 g., is crystallized from ethyl acetatehexane 1:1) as the title compound, white free-flowing crystals, m.p. l10.8-113.3 C. having R, 0.4 (TLC on silica gel in ethyl acetate-methanol) (9:1 1

EXAMPLE l0 p-acetylphenyl Ester of PGF a (Formula Ill-L) EXAMPLE 1 1 p-Benzoylphenyl Ester of PGF a (Formula lIl-M) Following the procedure of Example 1 but using 0.738 g. of PGF a, 0.291 ml. of triethylamine, 0.275 ml. of isobutylchloroformate, and 0.594 g. of phydroxybenzophenone, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-water (99:1 The residue obtained by concentration of selected fractions, 0.492 g., is crystallized from ethyl acetate diluted with three volumes of hexane as the title compound, white free-flowing crystals, m.p. 73.875.8 C., having R,0.5 (TLC on silica gel in ethyl acetate).

EXAMPLE l2 p-Carbamoylphenyl Ester of PGF a (Formula llI-N) Following the procedure of Example 1 but using 0738 g. of PGF a, 0.347 ml. of triethylamine, 0.326 ml. of isobutylchloroformate, and 0.433 g. of phydroxybenzamide, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-acetone (3:7). The residue obtained by concentration of selected fractions, 0.455 g., is crystallized from acetone diluted with an equal volume of acetonitrile as the title compound, white, free-flowing crystals, m.p. 129.5-130.8 C., having R 0.32 (TLC on silica gel in ethyl acetate-acetone (3:7)).

EXAMPLE 13 o-Carbamoylphenyl Ester of PGF oz (Formula Ill-O) p-(Methoxycarbonyl)phenyl Ester of PGF a (Formula Ill-Q) Following the procedure of Example 1 but using 0.738 g. of PGF2OL, 0.347 ml. of triethylamine, 0.326 ml. of isobutylchloroformate, and 0.474 g. of methyl p-hydroxybenzoate, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-water (99:1) followed by ethyl acetate-acetone-water (69:30zl The residue obtained by concentration of selected fractions, 0.678 g., is crystallized from ethyl acetate diluted with an equal volume of hexane as the title compound, white freeflowing crystals, m.p. 80.3-82.0 C., having R 0.3 (TLC on silica gel in ethyl acetate).

EXAMPLE 15 Z-Naphthyl Ester of PGF a (Formula lIl-X) Following the procedure of Example 1 but using 0.535 g. of PGF a, 0.254 ml. of triethylamine, 0.238 ml. of isobutylchloroformate, and 0.327 g. of ,B-naphthol, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate followed by acetonitrile. The residue obtained by concentration of selected fractions, 0.410 g., is crystallized from ethyl acetate diluted with 1.5 volumes of hexane as the title compound, white freeflowing crystals, m.p. 98.8100 C. having R; 0.25 (TLC on silica gel in ethyl acetate).

EXAMPLE 16 S-Sulfamoyl-l-naphthyl Ester of PGF a (Formula Ill-Y) Following the procedure of Example 1 but using 0.738 g. of PGF a, 0.347 ml. of triethylamine, 0.326 ml. of isobutylchloroformate, and 0.696 g. of lhydroxy-S-naphthalenesulfonamide there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting successively with ethyl acetate and ethyl acetate-acetone (1:1). The major fraction is chromatographed again, eluting with ethyl acetate-acetone (9:1 The residue obtained by concentration of selected fractions, 0.450 g., an oil, is the title compound, having R,0.4 (TLC on silica gel in ethyl acetate). 4

EXAMPLE l7 9-Oxofluoren 4-yl Ester of PGF a (Formula III-Z) Following the procedure of Example 1 but using 0.738 g. of PGF oz, 0.347 ml. of triethylamine. 0.326 ml. of isobutylchloroformate, and 0.612 g. of 4- hydroxy-9fluorenone, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetatewater (99:1 followed by ethyl acetate-acetone-water (:30:l The residue ob tained by concentration of selected fractions, 0.650 g., is crystallized from ethyl acetate-hexane (10:7) as the title compound, white free-flowing crystals. m.p. 83.886.8 C. having R 0.27 (TLC on silica gel in ethyl acetate).

Following the procedures of Examples l-17 but employing the racemic forms of the PG compounds, there are obtained the corresponding esters of racemic PG compounds.

EXAMPLES 18-78 including partitioning, solvent extraction, washing, sil-.

ica gel chromatography, trituration, or crystallization.

Following the procedures of Examples 18-78 but employing the racemic forms of the PG compounds, there are obtained the corresponding esters of the racemic 'PG compounds.

TABLE I Esters of PFG a Hydroxy Phenyl or Product PGF a Ex. Naphthyl Compound Ester of formula:

18 p-[ p-acctamidobenzamido Ill-C phenol l9 p-(p-henzamidobenzamido lll-D phenol 20 N(p-tritylphenyl)-p lll-P hydroxybenzamide 21 hydroquinone benzoate Ill-R 22 hydroquinone. p-acetamidollI-S benzoic acid ester 23 2.4-diacetamidophenol Ill-T 24 l-a :etamido-4-hydroxy Ill-U naphthalene 25 l-benzamido-4-hydroxylll-V naphthalene 26 l-hydroxy-4-ureido- Ill-W naphthalene TABLE II Esters of l5-Methyl-PGF a Hydroxy Phenyl or Product lS-Methyl- Ex. Naphthyl Compound PGF a Ester of formula:

27 p-acetamidophenol Ill-A 28 p-benzamidophenol lll-B 29 p( p-acetamidobenzamido llI-C phenol 30 p(p-benzamidobenzamido) lll-D phenol 31 p-hydroxyphenylurea lll-E 32 p-hydroxy-1,3-diphenylurea lll-F 33 p-phenylphenol 111-0 34 p-tritylphenol lllH 2. The ester of p-acetamidophenol and PGF a, a

PGF- a, a compound according to claim 1.

1 6. Free-flowing crystals of a compound of the formula:

wherein E is 

1. AN OPTICALLY ACTIVE COMPOUND OF THE FORMULA
 2. The ester of p-acetamidophenol and PGF2 Alpha , a compound according to claim
 1. 3. The ester of p-benzamidophenol and PGF2 Alpha , a compound according to claim
 1. 4. The ester of p-hydroxyphenylurea and PGF2 Alpha , a compound according to claim
 1. 5. The ester of p-hydroxy-sym-diphenylurea and PGF2 Alpha , a compound according to claim
 1. 6. Free-flowing crystals of a compound of the formula: 